The current Pilot and Feasibility (P &F) Study Program was initiated on June 1, 1989, when our Center formally changed from a P50 Liver Research Center that included Research Projects, Core Facilities and New Initiatives (much smaller in scope than P &F Studies and less funding per project) to a P30 Digestive Diseases Research Core Center. During the last ten years, we have supported 24 P &F Studies that have been completed and 4 additional projects that are currently in progress (see Progress Report, Exhibit VI). The projects were reviewed and rated for funding at the Annual Meeting of our Scientific Advisory Committee, comprised of five leading scientists from other institutions with expertise in relevant areas of liver research, along with one senior non-Center member of the Einstein faculty, Dr. Vern Schramm, Chairman, Department of Biochemistry, who serves as Liaison Officer with the Dean (see list below). The eligibility criteria to apply for a P &F Study were, and still are, precisely those defined in the guidelines. To be eligible, an Investigator must fall into one of the following three categories: 1) new Investigators to assist in development of their research program, 2) established Investigators in other fields of biomedical research to use their expertise for digestive diseases research, and 3) established Investigators in digestive disease research to allow exploration of possible innovative new directions of research that represent a significant departure from their ongoing, funded projects. Further details concerning the selection process for P &F Studies are provided below (see Management Plan). The Center has made extensive efforts over the years to recruit outstanding young Investigators from throughout the Albert Einstein College of Medicine and affiliated institutions for the P &F Study Program. As a policy, consistent with the P &F guidelines, we have been most interested in supporting applicants belonging to categories 1 and 2 (listed above). Of the 24 projects completed during the last ten years (see Exhibit VI), 12 (50%) were for new Investigators, 8 (34%) were for established Investigators working in other fields to bring their expertise to bear on liver-disease related projects, and 4 (16%) were for established Investigators in digestive diseases research to pursue new, innovative directions of research. To provide examples of P &F support in category 1 (new Investigators), Dr. Cohen was recruited to the Department of Medicine and Liver Research Center as Assistant Professor in 1997 with space and startup funds provided by the Liver Center, using resources provided by the College of Medicine. His initial P &F Study (6/97-5/99) was directed at studying the molecular biology and function of phosphatidyl choline transfer protein (PC-TP) in phospholipid metabolism and led to successful RO1 funding. In the next fiveyear cycle of Center funding, Dr. Cohen began to explore another new area on Scavenger Receptor Class B Type 1 (SR-BI)-mediated Cholesterol Trafficking in the Liver and submitted another P &F Study. The Scientific Advisory Committee judged the application to merit a second P &F Study Award for Dr. Cohen (6/01-5/03) under category 1, as he was still in the process of building his research program and transitioning from junior to senior status. Completion of this P &F Study led to a second NIH RO1 grant and thus, Dr. Cohen represents a strong example of the success of our P &F program. Subsequently, he was recruited to Harvard Medical School, Boston, MA, to become Director of Hepatology, Division of Gastroenterology at the Brigham and Women's Medical Center, Director, Harvard-MIT Division of Health Sciences and Technology, and Associate Professor of Medicine and Health Sciences and Technology of the Harvard-MIT M.D., Ph.D. Program. Dr. Ana Maria Cuervo was a new Investigator recruited as Assistant Professor to the Department of Anatomy and Structural Biology, again with space and start-up funds provided by the Liver Research Center. Her research had been in autophagy and she received a P &F Study to study the role of aging in impairing chaperone-mediated autophagy in the liver. A critical part of her P &F Study was to develop methods to study autophagy by RNA interference. She established these methods both in vitro and in vivo and has been extremely productive in her research on aging in the liver and brain, primarily in genetic disorders and Alzheimer's Disease. Dr. Cuervo is a rising star in autophagy resulting from protein misfolding and has received numerous awards and prizes for her outstanding research. She has most recently been funded as P.I. of a Program Project grant, collaborating with Dr. Mark Czaja, David Silver, Maureen Charron and others in the Liver Center on unique studies linking autophagy to obesity, lipid accumulation and steatohepatitis. Dr. Cuervo has become a leading, worldwide authority on chaperone-mediated autophagy in disease pathogenesis and aging. Dr. David Silver was recruited as Assistant Professor to the Department of Biochemistry to study regulation of lipid metabolism in the liver also with space and start-up funds provided by the Dean to the Liver Research Center. He recently cloned two unique genes, FIT-1 and FIT-2, that are evolutionary conserved from yeast to humans and are involved in lipid droplet formation. These genes play an essential role in hepatic triglyceride and lipid metabolism and their expression may be a central feature in obesity, steatohepatitis and diabetes mellitus. Initial characterization of these genes has recently been published in Proc. Nail. Acad. Sci. USA 105:94-99, 2008, patents (U.S. and worldwide) have been submitted and an RO1 grant on this work has recently been submitted to NIH. Among the 8 established Investigators in other fields (Category 2), Dr. P. Stanley brought her expertise in glycobiology to bear on projects related to liver membrane structure and function (collaboration with Drs. A. Wolkoff and R. Stockert) and mechanisms of hepatocarcinogenesis (collaboration with Dr. C. Rogler). Dr. R. Angeletti brought her expertise in proteomics to the Liver Center and has collaborated extensively with Drs. A. Wolkoff, D. Spray and P. Novikoff. Dr. K. Kim has brought a novel project to the Liver Center on developing state-of-the-art vectors to study hepatic stages of malaria and Dr. T. Evans, an expert on the role of transcription factors in early development, has been instrumental in bringing zebrafish and mouse ES cell technology to the Liver Center. As mentioned above, 4 established Investigators (Drs. C. Rogler, R. Stockert, M. Czaja and N. Theise) were also supported under this program (Category 3). Dr. C. Rogler was working on mechanisms of hepatitis B virus integration into the host genome in hepatocarcinogenesis. His P &F Study was to use newly developed microarray methods to identify genes that were regulated by HBV. This was an innovative, new direction of research for Dr. Rogler, and this technology was immediately transferred to the Molecular Biology and Genetics Core and used extensively by other Liver Center Investigators. Dr. R. Stockert was working on the biology of the asialoglycoprotein receptor and mechanisms of receptormediated endocytosis. His P &F Study was also in a completely new area, i.e., molecular mechanisms of hepatocyte infection with Dengue virus for which he subsequently received funding from US Army Medical Research and Material Command (8/15/02-8/11/06). Through a P &F Study, Dr. Mark Czaja began a new area of research concerning the relationship between insulin resistance and steatohepatitis. This research demonstrated that nonalcoholic fatty liver disease is associated with peripheral insulin resistance and hepatic oxidative stress, which is regulated by increased expression of cytochrome P4502E1. As part of this study, Dr. Czaja showed for the first time that chronic oxidative stress mediates lipid accumulation in the liver, as well as steatohepatitis. Together with Drs. Cuervo and Silver, he has shown that macroautophagy regulates hepatocyte lipid accumulation by mediating triglyceride metabolism and lipid droplet formation. This represents an entirely new concept regarding the mechanism(s) leading to fatty liver and steatohepatitis and is the major emphasis of a newly funded NIA Program Project grant in which Drs. Cuervo, Czaja, Silver and Charron will continue to collaborate. In the fourth P &F Study by an established Liver Center Investigator, Dr. Neil Theise was provided one year of support to expand, crossbreed and establish a colony of bitransgenic mice expressing histone 2B-GFP at high levels under control of the CK-19 promoter. In this bitransgenic mice model, histone 2BGFP expression is regulated by a tet-responsive element and can be turned off by doxycycline administration. Dr. Theise had just established this colony and needed support for its expansion and characterization, while he was continuing to apply for competing renewal funding of his NIH RO1 grant. Unfortunately, this grant was not refunded and the colony has been transferred to Dr. Mehboob Hussain, a collaborating investigator at Johns Hopkins University School of Medicine.